The primary objective of my research is to gain a better understanding of the basic
mechanisms underlying alcohol and oxidative stress-induced damage to the developing
brain. The pro-oxidant effects of ethanol have been documented in adult and fetal
tissues (brain and liver) using in vivo models and in primary cultures of fetal rat
cortical neurons and neonatal rat cortical astrocytes. Current studies are focusing
on the accelerated apoptotic death of neurons exposed to alcohol with mitochondria
as the source of reactive oxygen species and astrocyte-mediated protection from this
apoptotic death. Findings in our laboratory have illustrated that the well- documented
increase in neuron death in the ethanol-exposed developing brain may be due to enhanced
mitochondrially-mediated apoptosis (intrinsic pathways). Confocal and multiphoton
imaging of live fetal cortical neurons have illustrated that ethanol can elicit an
increase in reactive oxygen species within only minutes of exposure and that this
is associated with decreased levels of the antioxidant, glutathione. New findings
illustrate that astrocytes provide protection against this oxidative stress-induced
apoptotic death by maintaining neuron glutathione homeostasis. The system that provides
this neuroprotection can be up-regulated at, at least four points, each of which is
mediated by an “antioxidant response element” (ARE). This transcriptional-level regulation
can be manipulated and studies are ongoing to adapt this to controlled neuroprotection.
Additionally, the latter system is present in human and non-human primate cells and
investigations are addressing the species variations in these anti-oxidant control
mechanisms.

Another line of research (but connected to the above) addresses the role of ethanol-mediated
alterations in methylation of CPG islands in the promoter region which regulates transcription
of the NR2B gene. The latter is impacted by exposure of cultured cerebral cortical
neurons to chronic intermittent ethanol.

In summary, current studies address oxidative stress-mediated apoptotic neuron death
in the developing brain, the role of glutathione antioxidant systems in protection
against this, glia-mediated neuroprotection, and epigenetic mechanisms underlying
ethanol-related alterations in expression of the NR2B gene.

For a complete list of publications by George Henderson in PubMed, click here